This study prospectively investigated in hypertensive patients with type 2 diabetes the hypothesis that bedtime treatment with ≥1 hypertension medications exerts better blood pressure control and CVD risk reduction than conventional therapy, in which all medications are ingested upon waking. The results document, first, greater ambulatory blood pressure control in patients ingesting ≥1 hypertension medications at bedtime than in those ingesting all their medications upon awakening. The main differences between groups in terms of blood pressure control were achievement in patients treated at bedtime of 1
) significantly lower asleep blood pressure mean and 2
) greater sleep time relative blood pressure decline, without loss of awake blood pressure lowering efficacy (). These administration-time–dependent effects on sleep time blood pressure control were strongly associated with lower CVD risk and increased event-free survival. Indeed, the progressive reduction in the asleep blood pressure mean from baseline was the most significant predictor of survival. Moreover, lack of sleep time blood pressure control with reference to established ABPM criteria (18
) was the most prevalent factor among subjects with documented CVD events. As documented in a series of prospective trials reviewed elsewhere (1
), and also corroborated in the long-term evaluation provided here, treatment at bedtime is the most cost-effective and simplest strategy of successfully achieving the therapeutic goals of adequate asleep blood pressure reduction and preserving or reestablishing the normal 24-h blood pressure dipping pattern. One could thus conclude that the increased event-free survival associated with bedtime chronotherapy with ≥1 blood pressure–lowering medications, compared with upon-waking treatment of all medications, is linked to better achievement of these novel hypertension therapeutic goals.
Therapeutic intervention in hypertension consists of adequate control of blood pressure, the goal being to reduce/avert CVD morbidity and mortality. Blood pressure control has been defined so far on the unique basis of lowering blood pressure level (mainly if not exclusively determined conventionally at the clinic), without paying attention to potential alterations in the circadian blood pressure pattern due to treatment. Some of these studies found that too high a reduction in clinic blood pressure might be associated with increased CVD risk, whereas moderate reduction in blood pressure would decrease it; such association is known as the J-shaped or U-shped effect (21
). We also found a J-shaped association in the relation between achieved clinic blood pressure and CVD risk (, bottom
). However, the relation between achieved asleep blood pressure mean and CVD risk (, top
) presented a highly significant lower CVD risk associated with progressive diminished asleep blood pressure mean. Moreover, the amount of the asleep blood pressure reduction during follow-up was significantly correlated with increased number of patients treated at bedtime. One needs to realize that 1
) most marketed medictions do not provide homogeneous long-lasting efficacy throughout the entire 24 h, 2
) no marketed hypertension medication provides greater reduction of asleep than awake blood pressure when administered in the morning, and 3
) increasing the number of hypertension medications administered in the morning may lead to more intensive clinic blood pressure reduction but also to a progressive reduction in the sleep time relative blood pressure decline toward a more nondipper blood pressure pattern as a consequence of the greater reduction in awake than asleep blood pressure (1
). We thus conclude that the actual controversy on the possible J-shaped relation with CVD risk, described so far only for clinic blood pressure determined in patients presumably treated in the morning (21
), might not apply (when avoiding nocturnal hypotension) to asleep blood pressure mean, a more significant predictor of CVD morbidity and mortality that can be cost-effectively modified by proper-timed treatment (1
), as also documented here in patients with type 2 diabetes.
In conclusion, in hypertensive subjects with type 2 diabetes, we recommend taking into account the variable of treatment time with respect to the 24-h rest-activity pattern of each patient. Our findings document that a bedtime schedule with ≥1 blood pressure–lowering medications, in comparison with a schedule in which all such medications are ingested upon awakening, not only improves blood pressure control and decreases the prevalence of nondipping, but it significantly reduces CVD risk. Our results also document for the first time that reducing the asleep blood pressure mean while avoiding nocturnal hypotension, a novel therapeutic target requiring proper patient evaluation by ABPM, significantly decreases CVD morbidity and mortality in patients with type 2 diabetes.